P.367Comparative analysis of single stranded rAAV vectors expressing human SMN1 in correcting spinal muscular atrophy in mice

Abstract

Spinal muscular atrophy (SMA) is the most frequent genetic cause of infant death. It is an autosomal recessive neuromuscular disorder due to mutations in the SMN1 gene, leading to a selective loss of spinal cord -motor neurons and proximal muscle weakness. Remarkable progress has been made in the last years on the development of therapeutic approaches for SMA, including gene therapy. In particular, intravenous administration of self-complementary (sc) recombinant AAV9-SMN1 vectors have shown efficacy in several animal models and a clinical trial in type 1 SMA patients. In the present study, we evaluated the therapeutic efficacy of single stranded (ss) rAAV9 vectors expressing the human SMN1 coding sequence under various regulatory sequences in the Smn2B/- mouse model. Vectors were administrated by a single intracerebroventricular (ICV) injection at 8E12 vg/kg in newborn mice and compared for phenotype rescue. The ssAAV9-SMN1 vectors were able to increase the survival rate of Smn2B/- mice up to 1 year with differences in the median lifespan, compared to 26 days in non-treated mutant mice. Notably, this treatment increased the number of spinal motor neurons and improved the morphology of neuromuscular junctions close to normal. These results demonstrate the importance of regulatory sequences in vector design and the feasibility of SMA gene therapy by administration of ssAAV-SMN1 vectors.